Derivatives of 6-(gamma-dialkylamino)alkoxy 4,7-dimethoxy benzofuran

ABSTRACT

1. A COMPOUND OF THE FORMULA   4-(H3C-O-),5-((R3,R4-PHENYL)-CH2-CH2-CH(-OH)-),6-(R1-   N(-R2)-(CH2)N-O-),7-(H3C-O-)-BENZOFURAN   WHEREIN   -N(-R1)-R2   IS PYRROLIDINO, PIPERIDINO, MORPHOLINO OR PERHYDROAZEPINO; R3 AND R4 EACH IS H, HALOGEN, OH OR ALKOXY HAVING 1 TO 4 CARBON ATOMS, R3 AND R4 BEING THE SAME OR DIFFERENT OR R3 TOGETHER WITH R4 BEING METHYLENEDIOXY; AND N IS 2 OR 3 AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.

US. Cl. 260--293.58 7 Claims ABSTRACT OF THE DISCLOSURE Compound of the formula OCH in which R, and R are alkyl of 1 to 4 carbon atoms or is pyrrolidino, piperidino, morpholino or perhydroazepino;

R and R are H, halogen, OH, alkoxy having 1 to 4 carbon atoms, or R or R together form methylenedioxy; and n is 2 or 3.

The compounds are prepared by reducing the corresponding cinnamoyl compounds when R and R are not OH. When R and/ or R are OH, the corresponding cinnamoyl compound is converted to the phenate and then reduced. The compounds possess vasodilatatory, hypotensive, diuretic, spasmolytic, sedative, analgesic, anti-inflammatory, anti-histaminic, anti-ulcerous, anti-angiotensive and anti-hypertensive properties.

The present invention relates to new derivatives of 6- -dialkylamino) alkoxy 4,7-dimethoxy benzofuran, their method of preparation and their therapeutical application.

More particularly, the new compounds according to the present invention are 6-('y-dialkylamino) alkoxy 4,7-dimethoxy -(1-hydroxy 3-phenyl l-propy1) benzofurans of the formula:

H @cm-om+- R4 R 0H OCH; R2

the groupN(R ,R represents a dialkylamino group, an alkyl group containing from 1 to 4 carbon atoms or a heterocyclic ring system selected from amongst the following: pyrrolidino, piperidino, morpholino and perhydroazepino;

the radicals R and following substituents: a hydrogen atom, a halogen atom, a hydroxy group and an alkoxy group containing 1 to 4 R each are one selected from the United States Patent carbon atoms, R, and R possibly being identical or together forming a methylenedioxy bridge;

- n is 2 or 3.

When R and/0r R represent a substituent other than a hydroxy group, the method of preparation according to the invention consists in reducing a compound of the formula:

R (II) with sodium or potassium borohydride (4 moles) in the presence of pyridine (4 moles) in an alcoholic medium.

When R and/or R represent a hydroxy group, the compound of Formula II is firstly converted into a phenate in an ethanolic medium, the phenate thereafter being reduced in the manner described above. In either case, the compounds obtained can be converted into their salts with maleic, oxalic or fumaric acid.

The present invention also relates to therapeutical compositions comprising a compound of the formula I in association with a therapeutically acceptable carrier.

The invention will be further described, by way of example, with reference to the following non-limitative Examples which illustrate the method of preparation of the compounds.

EXAMPLE I 6-piperidinoeth0xy 4,7-dimethoxy 5-(1-hydr0xy p-methoxy-plzenyl-S '1 -pr0pyl benzofuran Reference No. 7146 To a solution of S-(p-rnethoxy cinnamoyl)6-(B-piperidino) ethoxy 4,7-dimeth0xy benzofuran (0.14 mole) in methanol or ethanol ml.) also containing pyridine (0.56 mole) and several drops of concentrated sodium hydroxide, there is added, over a period of 15 minutes, at room temperature, a solution of sodium or potassium borohydride (0.56 mole) in methanol or ethanol ml.), stabilised by 3 or 4 drops of concentrated sodium hydroxide. The temperature of the reaction medium rises by several degrees. The mixture is heated under reflux for 5 hours and the solvents then distilled ofi? under reduced pressure. A semi-crystalline yellow compound is obtained which is extracted with ethyl acetate and washed with water until neutral. The compound is then dried. A yellow oil is obtained which is crystallised in hexane.

Melting point 70 C. Yield 66% Empirical Formula C H NO Elementary analysis C H N Calculated percent 69.06 7.51 2.98 Found percent 69.09 7.31 3.12

EXAMPLE 2 6-(fi-dimelhylamino)ethoxy 4,7-dimeth0xy 5[1'-hydr0xy 3'-(2"-hydr0xy 3"-meth0xy phenyl) 1-pr0pyl)]benz0- furan Reference No. 71233 To a solution of 5-(2-hydroxy 3'-methoxy cinnamoyl) 6-(B-dimethylamino) ethoxy 4,7-dimethoxy benzofuran (0.25 mole) in ethanol (100 ml.) also containing pyridine (1.25 mole) and concentrated sodium hydroxide (25 ml.), there is added, under nitrogen, over a period of 15 minutes a solution of sodium or potassium borohydride 3 (1.25 mole) in ethanol (400 ml.) stabilised by 3 or 4 drops of concentrated sodium hydroxide.

The temperature of the reaction mixture rises by about ten degrees. The mixture is then heated under reflux for 7 hours. The solvents are removed, and the residue taken The compounds shown in Table I below have been prepared according to the method given in detail in Example I with the exception of the compounds referenced 71251, 71293, 71247, 71262, 72165, 72179, 72157, 72212, 72218, 72248, 72178, 71544, 72169, 72170, 72249, 72199 up in water (1 liter) and neutralrsed with concentrated and 72225, all of whrch prepared according to the method hydrochloric acid. The product is precipitated, filtered described in Example 2. and recrystallised from ethyl acetate. The compounds of formula (II) used as starting ma- Melting point 154 C. terials have been described in French Patent Application Yield 71% 10 No. 6,921,213 (published under No. 2,014,524) filed in Empirical Formula C2 H NOq our name on th June 1969 and entitled: New De- Eleme ntary analysis rivatives of 5-Cinnamoy1 Benzofuran, Their Method of C H N Preparation and Their Utilisation in Therapeutics. Calculated percent 64.70 7.01 3.14 Found percent 64.90 7.04 3.30 5

TABLEI l om-om-c R4 0H N- oH.)..-o 0 R2 OCH:

R Elementary analysis, percent Melt- N- ing Molec- Calculated Found Reference Yield, point, Empirical ular No. R, R3=R4 71 Form percent; C. formula weight 0 H N C H N 7178 on; H 2 Oxalate- 53 92 CIEHMN 0 489.51 61.34 6.38 2.86 61.35 6.54 2.95

71246 0&1. H 2 Base--.: 62 CNHBIN 0, 427.52 70.23 7.78 3.28 70.99 7.74 3.17

CgHs 70429 H 2 Oxalate- 67 128 CnHaaN 05 515.54 62.90 6.45 2.72 62.96 6.29 2.87

71210 H 2. d0. 70 139 CNHJEN 09 529.57 63.50 6.66 2.65 63.58 6.62 2.81

7185 H 2 do....- 89 176 C27HaaN 010 531.54 61.01 6.26 2.64 61.21 6.25 2.62

71252 H 2. 1o..... 62 138 C79H91N 0| 543.59 64.07 6.86 2.58 64.21 6.89 2.57

R1 Elementary analysis, percent Melting Molee- Calculated Found Reference Yield, point, Empirical ular No. R; R3 R4 75 Form percent C. formula weight 0 H N C H N 70383 0E3 H 4 OH- 2 Oxalate. 82 110 CzuHuN 010 519.53 60.10 6.40 2.70 60.22 6.42 2.90

7112 Gilt H 4-GHaO- 2 Base. 52 CuHasN 0| 457.55 68.25 7.71 3.06 68.07 7.65 3.19

CQHB 71169 ..iso CaH1\ H 4-oH=0- 2.-.do-.... 23 70 CzaHaoN 0| 485.60 69.25 8.10 2.88 69.45 8.02 3.07

7145 \N H 4-CH;O 2 do 58 67 c HaaN 01 455.53 08.55 7.30 3.08 08.50 7.24 3.08

7184 H 4011;0- 2 Oxalate- 102 C Hs N 011 561.57 59.82 6.28 2.49 60.03 6.53 2.60

71292 CE: H 4CH30 3 Base-... 15 CmsHaaN 0| 443.52 67.70 7.50 3.15 67.50 7.30 3.31

TABLE I-Continued R; M It Elementary analysis, percent 9 a -N ing Molec- Calculated Found Reference Position of Yield, point, Empirical nlar No. R; groupOH percent C. formula weight H N C H N 72157 Ortho 70 150 C25H31N0l 441.51 68.01 7.08 3.17 68.02 7.12 3.22 70 138 CHHHINOQ 441.51 68.01 7.08 3.17 68.20 7.16 3.07 46 149 CzaHaiNOt 441.51 68.01 7.08 3.17 67.85 7.24 3.37

74 131 C2sHa1NO1 457.51 65.63 6.83 3.06 65.59 6.84 3.20 90 159 Cz5Ha1NO1 457.51 65.63 6.83 3.06 65.81 6.90 3.21 54 140 CH31N01 457.51 65.63 6.83 3.06 65.72 6.84 3.26

65 166 CzeHasNOc 455.53 68.55 7.30 3.08 68.67 7.46 3.23 78 148 CZoHaINOe 455.53 68.55 7.30 3.08 68.54 7.50 3.08

81 143 C21H35N0u 469.56 69.06 7.51 2.98 68.98 7.58 3.18 75 130 Cz1Hz5NO0 469.56 69.06 7.51 2.98 69.01 7.66 3.05 153 C27HaaNOe 469.56 69.06 7.51 2.98 68.90 7.64 3.11

Plus 16 mole of iumarie acid.

The compounds of formula (I) have been studied on laboratory animals and have shown vasodilatatory, hypotensive, diuretic, spasmolytic, sedative, analgesic, antiinflammatory, antihistaminic, anti-ulcerous, antiangiotensive and anti-hypertensive properties.

1. Vasodilatatory properties (a) The compounds of formula (I) are capable of increasing the flow of the coronary vessels of the isolated heart of a guinea pig when they are added to the perfusion liquid of this organ.

By way of example, the results obtained with different compounds of formula (I) are given in Table H.

TABLE II Percentage Concentration increase in the introduced into flow of the Reference No. of the perfusion isolated heart compound tested liquid g/ml.) of a guinea pig (b) Moreover the compounds of formula (I) are capable of relaxing the spasm in the isolated artery of a rabbit caused by depolarisation by potassium chloride.

By way of example, the doses of certain compounds which inhibit this effect by 100% are given in Table III.

(c) Finally, administered intraarterially in doses which do not eifect the arterial pressure, the compounds of formula (I) cause an increase in the flow of the femoral artery to the level at which the injection is eifected in the anaesthetised dog with carotido-femoral anastomosis, the

measurement being eflected by means of a rotameter placed at the level of the derivation.

The results obtained with certain of these compounds are given in Table IV.

TABLE IV Dose adminis- Increase in the Reference No. of tered, g./kg./ femoral flow, compound tested 1 I percent 2. Hypotensive properties Administered intravenously into an anaesthetised rat or cat the compounds of formula (I) cause a lowering of the arterial pressure.

The results obtained with certain of these compounds are given in Table V.

TABLE V Reduction in arterial pressure Reference N o. of Dose admin- Intensity, Duration, compound tested istered Animal percent min.

3. Diuretic properties The compounds of formula (I) administered orally, into either a mouse or a rat, simultaneously with an isotonic solution of sodium chloride (1) ml. per 25 g. body weight in the case of a mouse and 2.5 ml. per 100 g. body weight in the case of a rat) are capable of causing an increase in the volume of urine passed with respect to the reference level, this volume being measured during the four hours following administration.

The results obtained with certain of these compounds are given in Table VI.

4. Spasmolytic properties The compounds of formula (I) introduced into the survival medium are capable of opposing the contractural action of barium chloride and acetylcholine on the isolated duodenum of a rat. This activity is estimated using papavcrime and atropine as standards.

The results obtained with certain of these compounds are given in Table VII.

TABLE VII Reference No. of Spasmolytic activity compounds tested x papaverine 70322 4 70383 7 5. Sedative properties The compounds of formula (1) administered orally to a mouse reduces the number of explorations in the evasion enclosure.

By way of example, with a dose of 50 mg./kg/PO compound No. 71252 reduced the number of explorations by 60% and compound No. 71217 by 40%.

6. Analgesic properties The compounds of formula (I) administered orally to a mouse are capable of reducing the number of painful stretchings caused by the interperitoneal injection of acetic acid.

The results obtained with certain of these compounds are given in Table VIII.

TAB LE VIII Reduction in the number of Dose adminispainful Reference No. of tered, mg./kg./ stretchings, compounds tested P 0 percent 7. Anti-inflammatory properties These properties show themselves by a diminution of the local oedema caused by the sub-planar injection of a phlogogenic agent, such as carrageenin, in a rat followed by the oral administration of the compounds of formula (I).

By way of example, the administration of 50 mg./kg./ P0 of compound No. 72157 causes a percentage reduction in the sub-planar oedema equal to 50%, whilst with the same dose, compound No. 71256 reduces the oedema by 70%.

8. Antihistaminic properties The compounds of formula (I) introduced into the survival medium are capable of opposing the contracturating effect of histamine on the isolated ileum of a guinea pig. This activity is determined taking promethazine as a standard.

By way of example, the antihistaminic activity of compound reference No. 71247 is equivalent to that of promethazine whilst that of compounds reference Nos. 72249 and 72225 are equivalent to 0.1 times that of promethazine.

9. Anti-Ulcerous properties The compounds of formula (I), administered intraduodenally reduce the extent of gastric ulcers caused in a rat by tying of the pylorus. (Shay Ulcers).

By way of example, the results obtained by administration of different compounds of formula (I) are given in Table IX.

TABLE IX Percentage re- Dose adminisduction of the Reference No. of tered, (mg. /kg./ Shay ulcer, compounds tested ID) percent 10. Antiangiotensive properties The compounds of formula ('I) are capable of reducing the contractions of the isolated ileum of a guinea pig caused by angiotension. By way of example, the compounds reference Nos. 72170, 72225 and 72169 have a DE equal to 0.7 gJml, 0.3 ,ugjml. and 0.3 ,ug./ml. respectively.

11. Antihypertensive properties The compounds of formula (I) administered orally into a hypertensive rat, are capable of lowering the systolic arterial pressure. By Way of example, the administration of different compounds of Formula (I) gives the results shown in Table X.

As is shown by the comparison between the doses given hereinbefore and the results given in Table XI hereinafter the difference between the pharmacologically active doses and the lethal doses is suflicient to allow the utilisation of compounds of formula (I) in therapeutics.

TABLE XI Dose administered Given intraveinously,

mg./kg.

Reference No. of compounds tested Percentage Given ora y, nanny The compounds of formula (I) are suitable for use in the treatment of circulatory disorders, hypertensions, oedemas, spasms of various types, excitement and pains, in particular, inflammations, those of allergies and gastroduodenal ulcers.

They are administered orally in the form of tablets, sugar coated pills or containing 20 to 250 mg. of active constituent (1 to 5 per day) and in the form of drops closed at 0.1 to 2% (20 drops, three times a day), rectal- 12 ly in the form of suppositories containing 20 to 150 mg. of active constituent (1 to 2 per day) and parenterally in the form of injectable ampoules containing 10 to 150 mg. of active constituent (1 to 2 per day).

What we claim is: 1. A compound of the formula gbawhg wherein is pyrrolidino, piperidino, morpholino or perhydroazepino;

R and R each is H, halogen, OH or alkoxy having 1 to 4 carbon atoms, R and R being the same or difierent, or R together with R being methylenedioxy; and

n is 2 or 3 and the pharmaceutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1 wherein at least one of R and R is methoxy, ethoxy, isopropyloxy or nbutoxy.

3. A compound as claimed in claim 1 wherein at least one of R and R is chlorine or fluorine.

4. A compound as claimed in claim 1 wherein at least one of R and R is hydroxy.

5. A compound as claimed in claim 1 wherein one of R and R is hydroxy and the other is hydrogen.

6. A compound as claimed in claim 1, in which R2 is piperidino, R is H, R; is p-hydroxyl and n is 2.

7. A compound as in claim 1, in which R, and R each is H, halogen, OH or alkoxy having 1 to 4 carbon atoms.

References Cited UNITED STATES PATENTS 3,555,047 1/ 1971 irmscher et a1. 260--345.5

G. THOMAS TODD, Primary Examiner US. Cl. X.R.

260247.7 G, 326.5 D, 346.2 R; 424248, 267, 274, 285 

1. A COMPOUND OF THE FORMULA 